Repetitive ischemia by coronary stenosis induces a novel window of ischemic preconditioning.
BACKGROUND
The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning.


RESULTS
To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6+/-3% after RCS and 16+/-3% after SWIPC (both groups P<0.05, less than shams 42+/-4%). Two molecular signatures of SWIPC, the increased expression of the inducible isoform of nitric oxide synthase and the translocation of protein kinase Cepsilon to the plasma membrane, were observed with SWIPC but not with RCS. Confirming this, pretreatment with a nitric oxide synthase inhibitor prevented the protection conferred by SWIPC but not by RCS. Microarray analysis revealed a qualitatively different genomic profile of cardioprotection between ischemic preconditioning induced by RCS and that induced by SWIPC. The number of genes significantly regulated was greater in RCS (5739) than in SWIPC (2394) animals. Of the 5739 genes regulated in RCS, only 31% were also regulated in SWIPC. Broad categories of genes induced by RCS but not SWIPC included those involved in autophagy, endoplasmic reticulum stress, and mitochondrial oxidative metabolism. The upregulation of these pathways was confirmed by Western blotting.


CONCLUSIONS
RCS induces cardioprotection against lethal myocardial ischemia that is at least as powerful as traditional ischemic preconditioning but is mediated through radically different mechanisms.
Shen
You-Tang
YT
Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
Depre
Christophe
C
Yan
Lin
L
Park
Ji Yeon
JY
Tian
Bin
B
Jain
Komal
K
Chen
Li
L
Zhang
Yan
Y
Kudej
Raymond K
RK
Zhao
Xin
X
Sadoshima
Junichi
J
Vatner
Dorothy E
DE
Vatner
Stephen F
SF
D000818:Animals; D003243:Consciousness; D003326:Coronary Circulation; D023921:Coronary Stenosis / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019157:Ischemic Preconditioning, Myocardial; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D012008:Recurrence; D013552:Swine
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051744:Protein Kinase C-epsilon